The primary mechanism of cytotoxicity of the chemotherapeutic agent CX-5461 is topoisomerase II poisoning
© 2020 National Academy of Sciences. All rights reserved. Small molecules can affect many cellular processes. The disambiguation of these effects to identify the causative mechanisms of cell death is extremely challenging. This challenge impacts both clinical development and the interpretation of ch...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Proceedings of the National Academy of Sciences
2021
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| Online Access: | https://hdl.handle.net/1721.1/136236 |
| _version_ | 1811087679445532672 |
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| author | Bruno, Peter M Lu, Mengrou Dennis, Kady A Inam, Haider Moore, Connor J Sheehe, John Elledge, Stephen J Hemann, Michael T Pritchard, Justin R |
| author2 | Koch Institute for Integrative Cancer Research at MIT |
| author_facet | Koch Institute for Integrative Cancer Research at MIT Bruno, Peter M Lu, Mengrou Dennis, Kady A Inam, Haider Moore, Connor J Sheehe, John Elledge, Stephen J Hemann, Michael T Pritchard, Justin R |
| author_sort | Bruno, Peter M |
| collection | MIT |
| description | © 2020 National Academy of Sciences. All rights reserved. Small molecules can affect many cellular processes. The disambiguation of these effects to identify the causative mechanisms of cell death is extremely challenging. This challenge impacts both clinical development and the interpretation of chemical genetic experiments. CX-5461 was developed as a selective RNA polymerase I inhibitor, but recent evidence suggests that it may cause DNA damage and induce G-quadraplex formation. Here we use three complimentary data mining modalities alongside biochemical and cell biological assays to show that CX-5461 exerts its primary cytotoxic activity through topoisomerase II poisoning. We then show that acquired resistance to CX-5461 in previously sensitive lymphoma cells confers collateral resistance to the topoisomerase II poison doxorubicin. Doxorubicin is already a frontline chemotherapy in a variety of hematopoietic malignancies, and CX-5461 is being tested in relapse/refractory hematopoietic tumors. Our data suggest that the mechanism of cell death induced by CX-5461 is critical for rational clinical development in these patients. Moreover, CX-5461 usage as a specific chemical genetic probe of RNA polymerase I function is challenging to interpret. Our multimodal data-driven approach is a useful way to detangle the intended and unintended mechanisms of drug action across diverse essential cellular processes. |
| first_indexed | 2024-09-23T13:50:17Z |
| format | Article |
| id | mit-1721.1/136236 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T13:50:17Z |
| publishDate | 2021 |
| publisher | Proceedings of the National Academy of Sciences |
| record_format | dspace |
| spelling | mit-1721.1/1362362023-09-13T17:29:24Z The primary mechanism of cytotoxicity of the chemotherapeutic agent CX-5461 is topoisomerase II poisoning Bruno, Peter M Lu, Mengrou Dennis, Kady A Inam, Haider Moore, Connor J Sheehe, John Elledge, Stephen J Hemann, Michael T Pritchard, Justin R Koch Institute for Integrative Cancer Research at MIT © 2020 National Academy of Sciences. All rights reserved. Small molecules can affect many cellular processes. The disambiguation of these effects to identify the causative mechanisms of cell death is extremely challenging. This challenge impacts both clinical development and the interpretation of chemical genetic experiments. CX-5461 was developed as a selective RNA polymerase I inhibitor, but recent evidence suggests that it may cause DNA damage and induce G-quadraplex formation. Here we use three complimentary data mining modalities alongside biochemical and cell biological assays to show that CX-5461 exerts its primary cytotoxic activity through topoisomerase II poisoning. We then show that acquired resistance to CX-5461 in previously sensitive lymphoma cells confers collateral resistance to the topoisomerase II poison doxorubicin. Doxorubicin is already a frontline chemotherapy in a variety of hematopoietic malignancies, and CX-5461 is being tested in relapse/refractory hematopoietic tumors. Our data suggest that the mechanism of cell death induced by CX-5461 is critical for rational clinical development in these patients. Moreover, CX-5461 usage as a specific chemical genetic probe of RNA polymerase I function is challenging to interpret. Our multimodal data-driven approach is a useful way to detangle the intended and unintended mechanisms of drug action across diverse essential cellular processes. 2021-10-27T20:34:24Z 2021-10-27T20:34:24Z 2020 2021-07-16T14:46:12Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/136236 en 10.1073/PNAS.1921649117 Proceedings of the National Academy of Sciences of the United States of America Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Proceedings of the National Academy of Sciences PNAS |
| spellingShingle | Bruno, Peter M Lu, Mengrou Dennis, Kady A Inam, Haider Moore, Connor J Sheehe, John Elledge, Stephen J Hemann, Michael T Pritchard, Justin R The primary mechanism of cytotoxicity of the chemotherapeutic agent CX-5461 is topoisomerase II poisoning |
| title | The primary mechanism of cytotoxicity of the chemotherapeutic agent CX-5461 is topoisomerase II poisoning |
| title_full | The primary mechanism of cytotoxicity of the chemotherapeutic agent CX-5461 is topoisomerase II poisoning |
| title_fullStr | The primary mechanism of cytotoxicity of the chemotherapeutic agent CX-5461 is topoisomerase II poisoning |
| title_full_unstemmed | The primary mechanism of cytotoxicity of the chemotherapeutic agent CX-5461 is topoisomerase II poisoning |
| title_short | The primary mechanism of cytotoxicity of the chemotherapeutic agent CX-5461 is topoisomerase II poisoning |
| title_sort | primary mechanism of cytotoxicity of the chemotherapeutic agent cx 5461 is topoisomerase ii poisoning |
| url | https://hdl.handle.net/1721.1/136236 |
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